A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells

  • Cell Metab. 2020 Feb 4;31(2):267-283.e12. doi: 10.1016/j.cmet.2019.11.020.
Hee Chan Yoo  1 ,  Seung Joon Park  2 ,  Miso Nam  3 ,  Juwon Kang  1 ,  Kibum Kim  2 ,  Joo Hye Yeo  1 ,  Joon-Ki Kim  4 ,  Yunkyung Heo  1 ,  Hee Seung Lee  5 ,  Myeong Youl Lee  6 ,  Chang Woo Lee  6 ,  Jong Soon Kang  6 ,  Yun-Hee Kim  4 ,  Jinu Lee  1 ,  Junjeong Choi  1 ,  Geum-Sook Hwang  3 ,  Seungmin Bang  5 ,  Jung Min Han  7
Affiliations
  • 1. Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon 21983, South Korea.
  • 2. Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon 21983, South Korea; Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 03722, South Korea.
  • 3. Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03759, South Korea.
  • 4. Research Institute of National Cancer Center, Goyang-si, Gyeonggi-do 10408, South Korea.
  • 5. Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea.
  • 6. Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk 28116, South Korea.
  • 7. Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon 21983, South Korea; Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 03722, South Korea. Electronic address: [email protected].
PMID: 31866442 DOI: 10.1016/j.cmet.2019.11.020
Abstract

Glutamine is an essential nutrient that regulates energy production, redox homeostasis, and signaling in Cancer cells. Despite the importance of glutamine in Mitochondrial Metabolism, the mitochondrial glutamine transporter has long been unknown. Here, we show that the SLC1A5 variant plays a critical role in Cancer metabolic reprogramming by transporting glutamine into mitochondria. The SLC1A5 variant has an N-terminal targeting signal for mitochondrial localization. Hypoxia-induced gene expression of the SLC1A5 variant is mediated by HIF-2α. Overexpression of the SLC1A5 variant mediates glutamine-induced ATP production and glutathione synthesis and confers gemcitabine resistance to pancreatic Cancer cells. SLC1A5 variant knockdown and overexpression alter Cancer cell and tumor growth, supporting an oncogenic role. This work demonstrates that the SLC1A5 variant is a mitochondrial glutamine transporter for Cancer metabolic reprogramming.

Keywords
ASCT2; HIF-2α; SLC1A5; SLC1A5 variant; cancer metabolism; gemcitabine resistance; glutamine; hypoxia; metabolic reprogramming; mitochondrial glutamine transporter.